JP3534130B2 - Pharmaceutical composition - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to solid pharmaceutical compositions. Particularly, it relates to granules and tablets in the pharmaceutical field.

[0002]

2. Description of the Related Art Many powder raw materials are compression-molded for the purpose of improving handleability and imparting functions. The most important property of a compression-molded product (tablet) is that it has a strength that does not cause abrasion or breakage during transportation or use. In addition to this property, tablets in the pharmaceutical field must have a short disintegration time in order to develop a rapid pharmacological effect after administration. The reason is that a typical tablet disintegrates in the digestive tract after taking, then the medicinal component is dissolved in the digestive tract fluid and absorbed from the digestive tract wall,
Since it dissolves in blood, circulates in the body, and exerts a pharmacological effect, the fact that the tablet disintegrates in the gastrointestinal tract immediately after taking the drug means that the pharmacological effect is expressed faster.

By the way, since many powder raw materials are not molded even when compressed, it is necessary to blend an excipient having compression moldability. Then, in order to impart a desired strength to the tablet, it is necessary to appropriately determine the compounding amount of the excipient and the compression molding force. Generally, the higher the amount of the excipient compounded and the higher the compression molding force, the higher the tablet strength. However, when it is desired to increase the compounding ratio of the main ingredient (powder raw material) in the tablet, for example, in the case of manufacturing a small tablet in the pharmaceutical field, the compounding amount of the excipient is significantly limited. In addition, excessive compression molding force is not preferable because it puts a load on the compression molding machine (tabletting machine) and accelerates wear of parts.

Further, when a film-coated granule and an excipient are mixed and tableted to obtain a tablet (such a tablet is referred to as a granule-containing tablet) or when an enzyme or an antibiotic is tableted. In order to prevent the damage of the film and the deterioration of the enzyme and the antibiotic, it becomes necessary to perform the molding with a lower compression molding force. Therefore, it is required that the amount of the excipient is smaller and the compression moldability is higher. Conventionally, crystalline cellulose has been known as an excipient used for such a purpose. Crystalline cellulose is one of the widely used excipients in the pharmaceutical field because it has high safety, high compression moldability, and good disintegration property.

At present, commercially available crystalline cellulose is, for example, Avicel <registered trademark> PH-1 manufactured by FMC in the United States.
01, PH-102, PH-105; Asahi Chemical Industry Co., Ltd.
Avicel <registered trademark> PH-101, PH-10
2, PH-301, PH-302, PH-F20, etc. are well known, and in addition to them, there are products such as those manufactured by Mingtai of the Republic of China, DMV of the Netherlands, manufactured by Rettenmeier of Germany, and Penwest of the United States. Are known. It is known that these commercially available crystalline celluloses show the highest compression moldability in excipients, but this compression moldability is not satisfactory, and there have been many calls for higher performance compression moldability.

The crystalline cellulose in the known literature has an average degree of polymerization of 15 to 375 and a bulk of 7 to 34 lb / f.
t ³ (1.84 to 8.92 cm ³ / g), particle size 300
Use of crystalline cellulose with a size of less than μm in pharmaceutical tablets has high tablet strength and improved disintegration (Japanese Patent Publication No. 40-
26274), the average degree of polymerization is 60 to 375, the apparent specific volume is 1.6 to 3.1 cm ³ / g, the apparent tapping specific volume is 1.40 cm ³ / g or more, and 200 mesh or more is 2 to 80%. It is preferable that crystalline cellulose having an angle of repose of 35 to 42 degrees has a high fluidity of the mixed powder when mixed with a main drug and an additive and has a rapid disintegration property when tableted (Japanese Patent Publication No. 56-2047, Japanese Patent Publication No. 56-38128) and the like are known.

The cellulose powder having moldability has an average degree of polymerization of about 450 to 650 and a compact apparent density of 0.40 to 0.60 g / cm ³ (1.67 to
2.50 cm ³ / g), and a cellulose powder having a mesh size of 200 mesh or less of 50% or more is an excipient suitable for tableting (Japanese Patent Publication No. 51-17172).
Specific average particle diameter (30 μm or less), specific surface area (1.3 m
⁽² / g or more) has high moldability (Japanese Patent Laid-Open No. 63-267731), has a specific crystal form (Cellulose I type), and has a porosity of pores having a diameter of 0.1 μm or more. Is 20% or more, and 350 mesh or more is 90% or more, the cellulose powder has high fluidity and moldability (Japanese Patent Laid-Open No. 1-272643), and the crystal form is I type, The total volume of pores with a surface area of 20 m ² / g or more and a diameter of 0.01 μm or more is 0.3 cm ³ / g
As described above, the cellulose powder having a particle size of 100 μm or less of 50% or more has high fluidity and high moldability (JP-A-2-84).
No. 401) is known.

However, as a result of careful examination of these, there was a problem that those having higher moldability had poor disintegration at the same time. Further, in order to improve the moldability of crystalline cellulose, it is effective to increase the apparent specific volume, and for that reason, crystalline cellulose is conventionally finely pulverized (Japanese Patent Laid-Open No. 63-267731) or cellulose powder. Various measures have been taken to make the particles porous so as to reduce the density of the particles themselves (Japanese Patent Laid-Open No. 2-84401). JP 63
The invention product described in Japanese Patent No. 267731 has a high apparent specific volume because it is a fine powder, but since the apparent tapping specific volume is low, it easily consolidates by compression and exhibits high compression moldability, but the gap between the tablets (water pipe) Since it also decreases, the disintegration property is extremely poor.

Similarly, the invention product described in JP-A-2-84401 has an extremely high specific surface area due to its porosity and an apparent high specific volume. Not only the crimping of but also the deformation of particles
Since compaction occurs and eventually the tablet gap (water conduit) is also reduced, the disintegration property is extremely poor.

[0010]

As described above, the conventional crystalline cellulose or cellulose powder has a problem that if the moldability is high, the disintegration property is poor, and if the disintegration property is good, the moldability is low. Therefore, an excipient that balances these properties has not been known. As mentioned above,
Excipients used in the pharmaceutical field have high moldability,
And it must have good disintegration.

[0011]

In view of the above situation, the present inventor has arrived at the present invention as a result of extensive studies on controlling the powder physical properties of crystalline cellulose to balance the moldability and the disintegration property. Is. That is, the present invention is: a pharmaceutical active ingredient powder, and a) an average degree of polymerization of 150 to
220, b) apparent specific volume of 4.0-6.0 cm ³ /
g, c) apparent tapping specific volume of 2.4 cm ³ / g or more, d) specific surface area of less than 20 m ² / g, e) acetic acid retention rate of 280% or more, and f) particles of 355 μm or more of 5% by weight.
And has a particle size distribution of less than 1 and an average particle size of 30 to 120 μm, and g) the compression characteristic represented by the following formula (1), and h)
Weigh out 500mg, then add 100kgf / c
The area of the bottom surface obtained when compressing at m ² for 10 seconds is 1
The cylindrical molded body of cm ² has a breaking strength in the diameter direction of 10 k.
Provided is a pharmaceutical composition containing crystalline cellulose having a compression molding property of gf or more and a disintegration time of 100 seconds or less. Also,

[Equation 2] (However, a = 0.85-0.90, b = 0.05-0.
10 and P is the compression pressure of the powder [kgf / cm
² ], V ₀ is the apparent specific volume of the powder [cm ³ / g], V is the specific volume of the powder or tablet at the compression pressure P [cm ³
/ G])

Crystalline cellulose has an adsorbed water content of 5 to 6
%, It also has a lateral relaxation time of adsorbed water of 0.00024 seconds or less (measured by a proton NMR spectrum method using a 1H solution NMR probe). It is also characterized in that the pharmaceutical composition is a tablet obtained by a direct powder compression method. Further, the pharmaceutical composition is a granule obtained by a dry granulation method,
Alternatively, it is also characterized in that it is a tablet obtained by compression molding the granules. Further, the pharmaceutical composition is a granule obtained by a wet granulation method,
Alternatively, it is also characterized in that it is a tablet obtained by compression molding the granules. It is also characterized in that the pharmaceutical composition is a tablet obtained by compression molding crystalline cellulose described as a granule obtained by a dry granulation method or a granule obtained by a wet granulation method. The pharmaceutical composition is also characterized in that it is a tablet obtained by compression molding crystalline cellulose and other tablet raw material powder described as a granule obtained by a dry granulation method or a granule obtained by a wet granulation method. Have. Also,

Another feature is that a disintegrating agent and a fluidizing agent are used as the tablet raw material powder. It is also characterized in that the medicinal ingredient powder is a Chinese herb powder or a crude drug powder. It is also characterized in that (10) the pharmaceutical composition is a capsule obtained by a capsule filling method utilizing the compression moldability of powder. It is also characterized in that the pharmaceutical composition described in (11) -is a granule having a coating film.

The present invention will be described below. The crystalline cellulose used in the present invention has an average degree of polymerization of 150.
It should be in the range of 220. Average degree of polymerization is 150
If the amount is less than the above range, the moldability is insufficient, and if it exceeds 220, the fibrous property appears. When the average degree of polymerization is 180 to 220, a good balance between moldability and disintegration is obtained, which is preferable. The crystalline cellulose used in the present invention must have an apparent specific volume of 4.0 to 6.0 cm ³ / g and an apparent tapping specific volume of 2.4 cm ³ / g or more. Apparent specific volume is 4.0 cm
If it is less than ³ / g, the moldability will be reduced to 6.0 cm ³ / g.
If it exceeds, the fluidity of the powder is lowered, which is not preferable.
When the apparent tapping specific volume is less than 2.4 cm ³ / g, the tablet is compacted and the disintegration property is deteriorated, which is not preferable. The upper limit of the apparent tapping specific volume is automatically determined to be 6.0 cm ³ / g from the value of the apparent specific volume, and if it is less than this value, there is no particular problem, but preferably 2.4 to 3.3.
It is cm ³ / g.

The crystalline cellulose used in the present invention must have a specific surface area of less than 20 m ² / g as measured by the BET method (using nitrogen as an adsorbent). When the specific surface area is 20 m ² / g or more, the crystalline cellulose particles have to have pores with large diameter (about 0.01 μm or more) inside themselves, and the strength of the particles becomes weak, so that the tablets are compacted. This is not desirable because it will result in worsening of the collapse. The preferred range is 1 to 10 m ² / g, and more preferably 1.1 to 3.0 m ² / g. As mentioned above, conventionally, it has been tried to increase the apparent specific volume in order to improve the moldability of crystalline cellulose and the like, but since no consideration was given to the apparent tapping specific volume or specific surface area, the disintegration is said to deteriorate. It was causing a situation.

However, the present inventors have developed an original drying method, whereby the apparent specific volume, the apparent tapping specific volume,
It is possible to control the specific surface area within a specific range, and it has been possible to provide crystalline cellulose that has a balance between moldability and disintegration, which has not existed in the past, and can be applied to pharmaceutical compositions. It was. The crystalline cellulose used in the present invention must have an acetic acid retention rate of 280% or more. What is the acetic acid retention rate? Soak the sample powder in twice the weight of acetic acid (purity 95% or more) for 30 minutes at room temperature.
Next, this is a value indicating the amount of acetic acid that can be retained by the sample when the sample is centrifuged at 2000 G and the supernatant is removed.

Acetic acid is absorbed by the cellulose powder, but hydrogen bonds of free hydroxyl groups present in the amorphous region (this is generally
It does not have enough swelling power to dissociate keratinized tissue (R. HASEBE, K. MATSUMOTO,
H. MAEDA, Sen'i Gakkaishi, Vo
l. 12, p203-207 (1955)), and because the sample is densely applied by centrifugal force to limit the amount of acetic acid retained in the interstices of the particles, the acetic acid retention rate means the porosity of the particles themselves. It shows its strength. If the acetic acid retention rate of crystalline cellulose is less than 280%, sufficient moldability cannot be exhibited. A preferable range is approximately 280 to 360%.

When the particle size distribution of the crystalline cellulose of the present invention is measured by the sieving method, the fraction remaining on the sieve having a mesh size of 355 μm is 5% by weight or less, and the average particle size represented by cumulative 50% by weight. The particle size should be 30-120 μm. If the amount of the fraction remaining on the sieve having a mesh size of 355 μm exceeds 5% by weight, the mixing uniformity with other powders is impaired, which causes a practical problem. The average particle size is 3
If it is less than 0 μm, the amount of fine particles is too large, so that the flow as a powder is deteriorated and the disintegration property of the tablet is deteriorated, which is not preferable. Furthermore, if the average particle size exceeds 120 μm, the powder becomes coarse, which lowers the moldability and deteriorates the mixing property with other powder raw materials, which is not preferable.

The crystalline cellulose used in the present invention has the Kawakita formula (a = 0.85 to 0.90, b = 0.05).
.About.0.10).
Kawakita's formula (K.KAWAKITA, Y.TSUSUM
I, Bull. Chem. Soc. Japan, Vo
l. 39, no. 7, p1364-1368 (196
6)) is an empirical formula that represents the change in volume of the powder due to pressurization.
It is said that they agree particularly well. Crystalline cellulose is also one of the powders that agrees well with Kawakita's formula. Kawakita's equation is expressed by the following equation (1), a and b are constants, P is the compression pressure [kgf / cm ² ] of the powder, and V ₀ is the apparent specific volume [cm ³ / g] of the powder. , V represent the specific volume [cm ³ / g] of the powder (or tablet) at the compression pressure P.

[Equation 3]

In the case of crystalline cellulose, the larger the constants a and b, the higher the moldability, but in the present invention, the constant a is 0.85 to 0.90 and the constant b is 0.05 to 0.05.
It must be within the range of 0.10. If a and / or b is lower than this lower limit, the moldability is insufficient.
Further, if a and / or b is higher than the upper limit value, the compression of the tablet remarkably progresses due to compression and compression, and the disintegration property of the tablet is deteriorated.

A method for preparing a standard tablet will be described. To prepare standard tablets, use a mold as used in making potassium bromide tablets in infrared absorption analysis. However, since the pressure is not reduced during compression molding, such a structure is not particularly required, and a structure having only a metal die and a punch may be used. Further, it may be a one-sided compression type or a two-sided compression type. The compression surface of the punch needs to be flat and circular with an area of 1 cm ² in order to obtain a cylindrical molded body. Into such a mold, 500 mg of the substance of the present invention (including adsorbed water) was charged, compressed to 100 kgf / cm ² with a pressurizing device (hand press) equipped with a pressure gauge, and this pressure was maintained for 10 seconds. A standard tablet can be prepared by removing it from the mold. Compression, pressure retention, and depressurization can also be performed with a universal tensile compression tester (for example, Autograph manufactured by Shimadzu Corporation).

Next, a method of measuring the breaking strength and the disintegration time of a standard tablet will be described. As for the breaking strength, the side surface of a standard tablet (cylindrical shape) is sandwiched by two parallel surfaces, stress is applied, and the stress when the standard tablet breaks is defined as the breaking strength. One side of the standard tablet is compressed and the other side moves at a constant speed. The moving speed is 4 to 13 cm /
It's about a minute. For this measurement, a commercially available tablet hardness meter or the above-mentioned universal tensile / compression tester can be used. Disintegration time is measured using the Japanese Pharmacopoeia, 12th Edition, General Test Method, Tablet Disintegration Test Method. The crystalline cellulose used in the present invention has a breaking strength of 10 kgf or more and a disintegration time of 100 when a standard tablet is produced by the above method.
Within seconds.

As described above, the existing excipient has a long disintegration time when it has high moldability, and therefore an excipient having high moldability and excellent disintegration as in the present invention has not been known. Generally, it is said that the breaking strength of tablets is practically required to be about 4 kgf or more ("Drug form of pharmaceuticals (published by Ito Dental Publishing Co., Ltd.)" 1983, p157), and fast-dissolving tablets (after administration). It is required that the disintegration time of a tablet in which 75% or more of the drug is dissolved within 20 minutes for the purpose of promptly exhibiting a drug effect is within 15 minutes (“Development of pharmaceuticals, 11 volumes, formulation Unit operation and machinery (published by Hirokawa Shoten), 1989, p65). However, for example, it is necessary to compound a large amount of a drug having poor moldability, and
In the case of manufacturing cold medicines that require fast-dissolving tablets, existing excipients have a breaking strength of standard tablets of 10 kgf.
Since the disintegration time was not exceeded, the disintegration time was exceeded 100 seconds, or both, it was difficult to satisfy the two performances of the fast-dissolving tablet described above. The crystalline cellulose of the present invention solves such a problem.

That is, when the crystalline cellulose of the present invention is incorporated into a tablet formulation, a tablet having a higher tablet breaking strength than conventional excipients and excellent disintegration can be produced. When the strength of the standard tablet is 11 kgf or more, the strength of the tablet becomes high, which is particularly preferable. The crystalline cellulose used in the present invention needs to have a transverse relaxation time of adsorbed water of 0.00024 seconds or less measured by a proton NMR spectrum method when the water content is 5 to 6%. In general,
When the NMR spectrum of a solid sample containing adsorbed water is measured using a 1H solution NMR probe, one broad peak derived from adsorbed water is obtained. You can If this value exceeds 0.00024 seconds, the moldability is lowered, which is not preferable. The preferred range is 0.00015 to 0.0
It is 0024 seconds. The mechanism of the phenomenon that the compression moldability increases when the adsorbed water lateral relaxation time is short is not clear, but it is presumed as follows.

That is, the short relaxation time of adsorbed water means that the mobility of water molecules is more restricted, and therefore, there are more hydroxyl groups of the cellulose molecule that easily hydrogen bond with adsorbed water. Let's do it. One of the reasons why crystalline cellulose has high compression moldability is that when the crystalline cellulose particles are stressed and pressed against each other or other powder particles, the hydroxyl groups on the surface form hydrogen bonds through the adsorbed water. It is said to be because. Therefore, it is considered that the shorter the transverse relaxation time of adsorbed water, the larger the amount of hydroxyl groups that can contribute to compression molding, and the higher the moldability. Conventionally, the main objective of improving the compression moldability of powder was to densify under high pressure during compression. The invention is new.

The crystalline cellulose used in the present invention is obtained by subjecting crystalline cellulose particles obtained by acid hydrolysis or alkaline oxidative decomposition of a cellulosic substance to a wet state or water dispersion in which acid, alkali or decomposition products are scarcely present. It can be produced by subjecting to a state, heat treatment, and drying. When heat treatment is not carried out, it can also be produced by drying cellulose particles in a water-dispersed state in a state where they are spread on a support having a smooth surface. The cellulosic material used in the present invention has a crystal form of cellulose type I, and is a material generally called natural cellulose. As mentioned above, examples include substances such as refined wood pulp, bamboo pulp, cotton linter, and ramie as described above. The purity (α-cellulose content) thereof is preferably higher from the viewpoint of production yield and the like, and is preferably about 85% or more.

Acid hydrolysis is carried out by converting the cellulosic material into hydrochloric acid,
It is performed by immersing in an aqueous solution of a mineral acid such as sulfuric acid, nitric acid, phosphoric acid, and stirring for a predetermined time at a predetermined temperature. It is particularly preferable to use an aqueous solution of hydrochloric acid or sulfuric acid. The concentration of the aqueous mineral acid solution is preferably 0.1 to 18% by weight, particularly preferably 0.1%.
It is 2 to 10% by weight. Alkali oxidative decomposition is carried out by immersing a cellulosic substance in an aqueous solution of potassium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide or the like in the presence of oxygen, and stirring at a predetermined temperature for a predetermined time. . It is particularly preferable to use potassium hydroxide or sodium hydroxide.

The alkaline oxidative decomposition can also be carried out using an aqueous solution of an oxidizing agent such as sodium hypochlorite, periodic acid, hydrogen peroxide solution. A particularly preferred oxidant is sodium hypochlorite. The concentration of the alkaline aqueous solution or the oxidizing agent aqueous solution is 0.1 to 15% by weight, particularly preferably 0.5 to 10% by weight. Acid hydrolysis or alkaline oxidation decomposition is 60 to 140 ° C., preferably 90 to 140 ° C.
At a temperature of 130 ° C. for 10 to 180 minutes, preferably 20
~ 120 minutes. Cellulosic material and acid aqueous solution,
Alternatively, the weight ratio of the alkaline aqueous solution or the oxidizing agent aqueous solution (cellulosic material: aqueous solution) is 1: 5 to 1:30,
Particularly preferably, it is 1: 6 to 1:20. The acid hydrolysis or alkali oxidation decomposition is carried out in an air atmosphere or an inert gas atmosphere under atmospheric pressure or under pressure.

A manufacturing method when heat treatment is performed will be described. The cellulosic material is acid-hydrolyzed or alkali-oxidized by the method described above, and if necessary, mechanical treatment (milling, etc.) is performed before or after the hydrolysis to obtain cellulose particles. Since the cellulose particles contain unnecessary components such as acid and alkali in addition to water, they are removed and purified by filtration, centrifugal separation, membrane separation technique or the like. The thus-obtained cellulose particles are added with water as necessary to obtain a solid content concentration of 40% by weight or less, a pH at 25 ° C. of 5 to 8.5, an electric conductivity of 300 μS / cm or less in a wet state, or water. It is subjected to heat treatment in a dispersed state. As the water, not only pure water but also water containing a small amount of an organic solvent may be used. The particle size distribution of the cellulose particles is 15% or less when the volume-based particle size distribution is 5 μm or less when measured with a laser diffraction particle size distribution analyzer LA-500 manufactured by Horiba Ltd. after being appropriately diluted with pure water. 10 for 100 μm and above
% Or less is preferable. However, at this time, if ultrasonic dispersion is applied to the measurement sample, the particles may be broken and become small, so ultrasonic dispersion is not applied, and the refractive index of the device is set to "standard" for measurement.

If the particles having a particle size of 5 μm or less exceed 15%, the particles are strongly dried and shrunk at the time of drying, and the compression moldability is impaired. Also,
If the content of particles having a particle size of 100 μm or more exceeds 10%, fibrous properties appear in the product, which adversely affects the powder fluidity and the disintegration property of tablets. The solid content concentration of 5 to 23% by weight is particularly preferable because the heat treatment effect and the production efficiency are high. In the existing method for producing crystalline cellulose, for example, an aqueous dispersion of cellulose particles was heated at 100 ° C. or higher at the end of acid hydrolysis, but a large amount of acid and decomposition products exist. Since the structure change as described below cannot be taken, even if some structure change is caused, the structure will be destroyed because the purification step such as washing is always performed after that. The effect was not exhibited.

The heat treatment is carried out by a commonly used autoclave or heat exchanger for highly viscous fluid (for example, Shinko Pantech Co., Ltd.).
Manufactured by Freetherm Co., Ltd., etc., is about 100 ° C. or higher, preferably 100 to 200 ° C., more preferably 110 to 130.
It suffices if it is heated to ℃, and the temperature is maintained for a short time. However, cellulose particles in a wet state or in a water-dispersed state have very poor heat transfer, and thus it is difficult to raise the temperature. When using an ordinary autoclave, it is necessary to sufficiently lengthen the treatment time or sufficiently stir. . By such heat treatment, the cellulose particles interact with each other, or with hydrogen ions, hydroxide ions, water molecules, and the like. For example, an aqueous dispersion causes an increase in viscosity (gelation) and a decrease in pH. It is not clear what kind of structure it takes, but cellulose particles, hydrogen ions,
It is not difficult to imagine that hydroxide ions, water molecules, etc. associate and gel.

This structure does not break even when cooled to room temperature, but when it is lightly stirred with a glass rod or the like, the viscosity immediately decreases, and at the same time, the pH increases and returns to the state before the heat treatment. However, the essence of the heat treatment is not such a macroscopic gel structure but a more microscopic structural change. The reason is that even though the structure of the entire system is broken, soft aggregation of cellulose particles is observed, and it is considered that the association of particles is still maintained microscopically. Another evidence that the particles may be microscopically associated is the rate of water drying. The once-heat-treated aqueous dispersion of cellulose particles has a faster drying rate of 10% or more than the non-heat-treated one. The reason is that the particles are associated with each other and the dried product has a sparse structure, so that water diffusion is good. It is thought to be because.

After the heat treatment is performed in this manner, water is evaporated and dried by various methods. As a drying method, a usual method such as spray drying using a disk-type or air-based two-fluid nozzle type atomizer, and tray hot air drying can be used. This drying treatment may be performed after the cooling treatment is once performed, or may be continuously performed without cooling. "Continuous" here means
When simultaneously evaporating the water content and raising the temperature of the aqueous dispersion of cellulose particles, the step of raising the temperature to 100 ° C. or more in the presence of water and then ending the drying is included. However, the water content at this time may be in a gaseous state.

A preferred example of performing the heat treatment and the drying treatment at the same time is a method using a drum dryer or a belt dryer. Further, a method of spray drying with a two-fluid nozzle using steam of 100 ° C. or higher is also effective. When dried using a drum dryer, the aqueous dispersion of cellulose particles has a solid content (cellulose particles) concentration of 10 to 10.
23 wt%, pH at 25 ° C is 5 to 8.5, 25 ° C
It is preferable that the electric conductivity at is 300 μS / cm or less. The drying condition is that the drum surface temperature is 105.
The temperature is set to about 150 ° C., and the drum clearance, the drum rotation speed, the supply amount of the cellulose particle dispersion liquid, and the like are appropriately selected so that the water content of the dried product becomes about 3 to 5% at the end of drying. In the conventional spray drying method and hot air drying method, even if the blast temperature is 100 ° C or higher, the product temperature will be dried up to 100 ° C due to the latent heat of vaporization of water. It is different from the technique of the present invention in that the “heat treatment” is not performed.

Next, a manufacturing method in the case where no heat treatment is required will be described. The crystalline cellulose of the present invention can be produced by subjecting the cellulose particles in a water-dispersed state prepared by the above-mentioned method to a smooth support in a state where the cellulose support is dried, when the heat treatment is not applied. An aqueous dispersion of cellulose particles has a volume-based particle size distribution measured by a laser diffraction particle size distribution measuring apparatus LA-500 manufactured by Horiba, Ltd. of 5% or less of 15% or less, 100 μm or more of 10% or less (measurement sample If ultrasonic dispersion is applied to the particles, the particles may break and become smaller. Therefore, ultrasonic dispersion is not applied, and the refractive index of the device is set as "standard". .5, electric conductivity is 30
It should be 0 μS / cm or less.

The term “smooth support” as used in the present invention means a horizontal or curved surface that does not penetrate water and has no irregularities, and is preferably made of a material having good water wettability. "There are no irregularities" means that something like a ruler is diagonally attached to the surface (about 40
It is something that can be advanced without resistance when it is pressed and slid against the direction of travel, and the direction of travel is 1 cm.
On the other hand, the height difference is preferably about 5 mm or less.
Suitable examples include a glass plate, an aluminum plate and a stainless plate. The thickness when extended to the support depends on the solid content concentration: 13 mm or less when 16 wt% or more and 23 wt% or less, 2 m when less than 16 wt%
It is necessary to be m or less.

When the concentration is more than 23% by weight, drying shrinkage is strong and moldability is deteriorated. In the case of 16 to 23% by weight, if the thickness is 13 mm or less, a three-dimensional network of cellulose particles is formed in the entire aqueous dispersion, and the movement of the particles is restricted by the support. Since it is limited, that is, keratinization is suppressed, it exhibits extremely high moldability and excellent disintegration. When the amount is less than 16% by weight, a network of cellulose particles is not formed so much, so that when the thickness is large, convection of the cellulose particles occurs and strong drying shrinkage occurs. However, if the thickness is 2 mm or less, drying shrinkage does not occur probably because the resistance of the support plate is strongly received, and also extremely high moldability and excellent disintegration property are exhibited. There is no particular lower limit of the solid content concentration,
Considering the manufacturing efficiency, it is not preferable to have a very thin product,
It is preferably about 5% by weight or more. From the viewpoint of productivity and function, it is particularly preferable that the cellulose particle aqueous dispersion having a concentration of 16 to 19% by weight is spread to a thickness of 2 mm or less and dried. Further, when the above-mentioned aqueous dispersion of cellulose particles subjected to heat treatment is spread on a support and dried, the function of crystalline cellulose is improved, which is particularly preferable.

There is no limitation on the drying method, and room temperature drying, hot air drying, reduced pressure drying and the like can be used. Further, as a method for drying while stretching the support, a drum dryer or a belt dryer is used. it can. It is described in US Pat. No. 2,978,446 that a colorless and transparent film adhered to a glass plate is formed by spreading hydrolyzed cellulose on a glass plate and drying it. It was done merely to demonstrate the properties of hydrolyzed cellulose, and there is no disclosure of the concept of recovering this membrane and utilizing it as an excipient for compression molding. Further, according to the description of the patent, the size of the cellulose particles is as small as about 1 μm or less, and according to the study by the present inventor, such particles are keratinized, peeled and crushed. It does not show high moldability and excellent disintegration as in the present invention. The present invention exhibits a high function as an excipient for compression molding only by extending an aqueous dispersion of cellulose particles having a specific particle size distribution on a support and drying it. It is impossible to do.

Further, the fact that a drum dryer can be used for producing crystalline cellulose and the like is described in, for example, Japanese Examined Patent Publication No. 40-262.
As described in Japanese Patent Publication No. 74, the compression moldability is high, and
In order to produce crystalline cellulose having good disintegration, there is no description about the fact that an aqueous dispersion of cellulose particles having a specific particle size, electric conductivity, pH, and solid content concentration must be used, and it is conventionally known. There was no technology. The crystalline cellulose used in the present invention is a white, free-flowing powder. When the surface of one particle is observed with a high-resolution SEM, circular to elliptical pores of about 5 to 40 nm can be observed. I think that these pores contribute to high moldability and excellent disintegration property. The pores on the surface are clogged by repeated absorption and desorption of water vapor. However, the pores are maintained inside,
It can be observed by cleaving the particles.

The amount of crystalline cellulose blended to obtain the pharmaceutical composition of the present invention is 1 to 99% by weight. If the content of the crystalline cellulose is less than 1% by weight, sufficient moldability cannot be exhibited, and if it is more than that, there is no problem. A preferable blending amount is 3 to 90% by weight, and a particularly preferable blending amount is 5 to 50% by weight. The pharmaceutical composition of the present invention comprises a medicinal ingredient powder, the above-mentioned crystalline cellulose, and other additives. The blending amount of the pharmaceutical active ingredient powder is appropriately determined depending on the pharmaceutical active ingredient,
Generally, about 0.01 to 90% by weight is blended.

Instead of the medicinal ingredient powder of pharmaceuticals, pesticide ingredient powder, fertilizer ingredient powder, feed ingredient powder, food ingredient powder, cosmetic ingredient powder, coloring material powder, metal powder, ceramics powder, catalyst powder, perfume powder, surfactant. The same effect can be obtained by using powder or the like. These powders also include powders carrying a liquid such as oil. Pharmaceutically active ingredients include main ingredients that dislike water, main ingredients that are easily inactivated by compression pressure during compression molding (eg, digestive enzymes, peptides, antibiotics), a large amount of compounding agent The main effects of the present invention are greatly reduced in the present invention, such as main drugs having a small amount of herbs (eg, Chinese herbs, crude drugs, cold remedies) and main drugs which have a disintegrating property and require the addition of a large amount of disintegrant.

Examples of other additives (which are referred to as tablet raw material powders when used in the production of tablets), which are other compounding ingredients, are disintegrants (low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, cross carme). Loin sodium, crospovidone, sodium carboxymethyl starch, partially pregelatinized starch,
Hydroxypropyl starch, corn starch,
Wheat starch, rice starch, potato starch,
Etc.), binder ((anhydrous) lactose, mannitol, sorbit, crystalline cellulose, crystalline cellulose / carmellose sodium, synthetic hydrotalcite, precipitated calcium carbonate, magnesium metasilicate aluminate, (anhydrous) calcium hydrogen phosphate, etc. ), Lubricants (stearic acid, magnesium stearate, calcium stearate, synthetic aluminum silicate, dried aluminum hydroxide gel,
Talc, etc.), superplasticizer (hydrous silicon dioxide, light anhydrous silicic acid, etc.), colorant (yellow ferric oxide, food red No. 2, food green No. 3, copper chlorophyllin sodium, titanium oxide, etc.), taste masking Examples thereof include agents (sucrose, etc.), flavoring agents (cinnamon oil, peppermint oil, etc.), concealing agents (titanium oxide, etc.), and the like.

The pharmaceutical composition is in the form of tablets, granules, fine granules or capsules, and its size and shape are not particularly limited. For example, in the case of tablets, the diameter is 7 mm or less. Small tablets are effective. The main embodiment of the pharmaceutical composition in the present invention is molding by the direct powder compression method. The direct powder compression method is to mix powders of medicinal and pharmaceutical ingredients with various additives at once or in several batches, then fill the mixed powder in a mold (mill) and compress with a punch. This is a method for producing tablets. As the compression molding machine, a generally used single-shot tableting machine, rotary tableting machine or the like can be used. When the fluidity of the mixed powder is poor, it is preferable to use a forced feeder. At this time, the compounding amount of the crystalline cellulose used in the present invention is 5 to 70.
Preference is given to using% by weight, in particular 10-40% by weight.

The dry granulation method referred to in the present invention is a method for producing granules in which a mixed powder of a medicinal ingredient powder and an additive is compressed once, molded, and then crushed and granulated. .
The dry granulation method is a method for producing granules to be used as it is, and is also an intermediate step of the method for producing tablets by tableting the granules (dry granule compression method). In this dry granulation method and dry granule compression method, the medicinal active ingredient is hygroscopic, and
It is used when the wet granulation method or wet granule compression method cannot be used because it is unstable to heat or water, or when the direct powder compression method cannot be used because of poor fluidity or high bulk. Lactose as a binder in the dry granulation method and the dry granule compression method,
Mannitol, crystalline cellulose, etc. are often used, but even with conventional crystalline cellulose, which is said to have the highest binding property (compression moldability), from the viewpoint of generation of fine powder during crushing and lack of tablet hardness, Often more connectivity was required. The crystalline cellulose used in the present invention solves this problem.

The granules obtained by the wet granulation method and the granules obtained by the dry granulation method referred to in the present invention are the granules obtained by granulating the main component powder and additives by a known method, and having a particle size suitable for taking or tableting. It was prepared for distribution. The particle size distribution depends on the design of the final product (tablet size, degree of pore formation, etc.), but the size is 50 to 1700 μm, and the average particle size is about 100 to 800 μm. Is preferable from the viewpoint of fluidity.
The granulation method is, as an example of the wet granulation method, fluidized bed granulation method, crushing granulation method, stirring granulation method, liquid phase granulation method, tumbling granulation method, vacuum freezing granulation method, tumbling fluidization. The granulation method, the extrusion granulation method and the like can be mentioned, and the dry granulation method can include the compression granulation method and the melt granulation method. The tablet raw material powder is an additive as described above, and may be used by mixing it with a medicinal and pharmaceutical ingredient if necessary.

By the way, many powder raw materials are often fine powders, and it is difficult to perform compression molding by a direct compression method (direct compression method) because the powder has poor fluidity. Also,
In many cases, the powder raw material alone is not molded even if compressed. In such a case, the object is achieved by a method of granulating by wet or dry method and then compression molding (granular compression method). In particular, the wet granule compression method (wet pressing method) changes the granulation method (high-speed agitation granulation method, fluidized bed granulation method, etc.), the type and amount of the binding liquid, and so on. It is widely used because it can control fluidity, compression moldability, and disintegration property of tablets, which are compression molded products.
However, depending on the type and amount of powdered raw materials (medicinal medicinal ingredients, etc.) for tableting, the moldability and disintegration properties of tablets cannot be adequately controlled.

As one means for solving this problem, a method is used in which the granules for tableting are mixed with an additive imparting moldability and disintegration, and the mixture is subjected to tableting. Generally, this method is called "conventional method", and the method for producing granules is effective not only in the wet method but also in the dry method and other granulation methods. According to this method, the effect of the additive becomes more remarkable than when the granules are incorporated into the inside of the granules, and the tablet formability and disintegration can be satisfied. When the crystalline cellulose used in the present invention is used as an additive to be mixed with tableting granules, it exhibits unprecedented excellent moldability. further,
When the crystalline cellulose of the present invention as an additive to be mixed with tableting granules and a disintegrating agent which is one kind of tablet raw material powder and a fluidizing agent are mixed and used, a tablet having extremely excellent disintegration in addition to compression moldability is obtained. It becomes possible to manufacture. The disintegrant is a substance that absorbs water and swells itself to promote disintegration of the tablet, and examples thereof are as described above.

Croscarmellose sodium is particularly preferable, and examples thereof include "Ac-Di-Sol" (FMC
Company). The fluidizing agent is fine particles that adhere to the surface of large particles having poor fluidity to reduce the adhesive force between the large particles, and examples thereof are as described above. Light anhydrous silicic acid is particularly preferable, and examples thereof include "AEROSIL" (manufactured by Nippon Aerosil), "Carplex" (manufactured by Shionogi Pharmaceutical), "Syloid" (manufactured by Fuji Devison), "Adsolider" (manufactured by Freund Sangyo), etc. Can be mentioned. The blending amount is not particularly limited, but the crystalline cellulose of the present invention is 1
~ 30 wt%, disintegrating agent 0.5 ~ 20 wt%,
A suitable example of the fluidizing agent is about 0.1 to 5% by weight.

The present invention also provides a method for producing a tableting granule suitable for producing a tablet having the above-mentioned problem, that is, sufficient strength and disintegrability by a wet method. As the wet granulation method, similar to the above, a fluidized bed granulation method, a crushing granulation method, a stirring granulation method, a tumbling fluidized granulation method, an extrusion granulation method and the like can be used. Crystalline cellulose may be added to the raw material mixed powder. Since the crystalline cellulose used in the present invention has a low particle density, the granulated product (tabletting granules) becomes bulky and the compression moldability becomes high. Further, since the water absorbency is high, the granulation rate is slowed down even when granulating a medicinal component powder having high solubility in water, so that the generation of coarse particles is reduced and the granulation yield is improved. The blending amount is preferably 5 to 50% by weight, more preferably 7 to 40% by weight.
Is.

The present invention is very suitable for tableting Chinese herb powder and herbal powder. Herbal medicine powder is a mixture of herbal medicines according to a certain rule in accordance with the treatment of Chinese medicine, crushed into powder, and an extraction solvent such as water or ethanol. It means an extract powder that has been extracted and dried as it is or after being mixed with an excipient such as lactose. By the way, as an example of Chinese medicine,
There are 210 prescriptions for Kampo preparations for general use (“Handbook of Kampo preparations for general use”, supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, Yakuji Jikhosha (1981)) and the like. In addition, crude drug is grass root bark etc. obtained from nature used for medicine, crude powder is crushed and powdered, and the ingredients are extracted with an extraction solvent such as water or ethanol. , As it is, or after being mixed with an excipient such as lactose and dried, it is an extract powder.

As an example thereof, a powdered crude drug described in the 12th revised Japanese Pharmacopoeia Part 2 can be mentioned. In general, these powders should be of a size that they can be mixed with other excipients without segregation, which means that the largest particles should be approximately 355 μm or smaller, with a cumulative particle size of 50% by weight. Appropriate average particle size represented is about 10 to 150 μm. Despite the relatively large dose of Kampo and crude drug powders, it is required to make tablets of small size to make it easier to take, but in order to solve this problem by the direct powder compression method. Had to be blended with an excipient having higher moldability and good disintegration. Although it was difficult to obtain sufficient tablet strength by using conventional excipients including crystalline cellulose, this problem can be solved by using the present invention.

The present invention is also very suitable for tableting granules having a coating film. When granules with a coating film such as sustained-release coated granules and enteric-coated granules are compressed into tablets, the coating film is damaged by the compressive stress, and the dissolution rate of the medicinal active ingredient in the medium such as gastric juice. There were many phenomena that increased. Although it has been difficult to obtain sufficient tablet strength while lowering the tableting pressure by using conventional excipients including crystalline cellulose, this problem can be solved by using the present invention. The present invention makes it possible to form tablets without damaging the coating film by mixing the granules having the coating film, the crystalline cellulose used in the present invention, and optionally other additives, and compression-molding the mixture. is there. In this case, the larger the amount of crystalline cellulose used in the present invention is, the more effective it is in reducing coating film damage. However, in consideration of the amount of granules, 5 to 60% by weight is a preferable amount, and more preferable amount is more preferable. Is 10 to 50% by weight.

The present invention is also suitable for capsules manufactured by a filling method utilizing the compression moldability of powder. When the crystalline cellulose used in the present invention is blended in the raw material powder, the variation in the filling of the raw material powder is reduced, and thus the variation in the weight of the capsule is reduced. Further, the present invention is also extremely effective in the case where the medicinal active ingredient is altered due to the pressure during compression and the temperature rise due to adiabatic compression. The pharmaceutical composition of the present invention is used after being subjected to post-processing such as film coating, sugar coating and capsule filling, if necessary.

The crystalline cellulose used in the present invention is used in the pharmaceutical field in the same manner as the existing excipients. As described above for use in tablets, etc., other than that,
It may be incorporated into a powder for the purpose of preventing blocking and improving fluidity, or may be incorporated into a capsule for the purpose of improving filling properties. It can also be incorporated into a sugar coating liquid as a sugar coating reinforcing agent. Further, it can be used as a dispersion aid or an absorption aid for nasal medicine. INDUSTRIAL APPLICABILITY The present invention can be applied to those requiring high compression moldability, such as tablet type confectionery and health food in the food field, solid foundation in the cosmetic field, and catalysts in the ceramic field. Further, it can be applied to foods as dietary fiber and texture modifier.

[0055]

The present invention is described in detail below with reference to examples, but these do not limit the scope of the present invention. The methods for measuring the physical properties of the cellulose particle aqueous dispersions, powder samples and tablets in the examples and comparative examples, which have not been described so far, are as follows. -PH [-] Cellulose particle | grains aqueous dispersion is adjusted to 25 degreeC, and it measures with a glass electrode type hydrogen ion concentration meter (Toa Denpa Kogyo KK-made, pH meter HM-20E type). -Electrical conductivity [μS / cm] An aqueous dispersion of cellulose particles was adjusted to 25 ° C, and an electrical conductivity measuring device (manufactured by Yokogawa Electric Corporation, SC51POCKET) was used.
Type).

Acetic acid retention rate [%] About 3 g of a powder sample is precisely weighed and immersed in acetic acid (purity of 95% or more) about 10 times the weight of the sample for 30 minutes at room temperature. Then, the mixture is centrifuged at 2000 G for 10 minutes, and the supernatant is removed.
The weight (W) of the wet product of acetic acid thus obtained was measured, followed by vacuum heating and drying, and the weight (W ₀ ) of the dried product was measured.
The acetic acid retention rate is calculated by the following formula. However, the measurement was performed twice and the average value was taken. Acetic acid retention rate = 100 × (W−W ₀ ) / W ₀ · Compression characteristic (Kawakita's equation constants a and b) A powder sample 500 mg is precisely weighed to prepare a cylindrical molded body having a bottom area of 1 cm ^2. 200, 400, 800 with hand press
Compress to 1200, 1600 kgf / cm ² , hold at this pressure for 10 seconds, then remove tablets. A total of 50 tablets are produced at each pressure, a total of 50 tablets, the weight and thickness of each tablet are measured, and the volume reduction rate (C) of the powder is calculated from the following formula. C = (V ₀ −V) / V ₀ (where V ₀ is the apparent specific volume of the powder [cm ³ /
g], and V represents the specific volume of the tablet [cm ³ / g]. ) The relationship between the compression pressure P and P / C is linearly regressed by the method of least squares, and (P / C = S + P × T) From the slope T and the intercept S, the constants a and b of the following Kawakita equation are calculated. (A = 1 / T, b = T / S)

Particle size distribution and average particle size The particle size distribution of the powder sample is measured with a JIS standard sieve (Z8 by a low tap type sieve shaker (Sieve Shaker A type manufactured by Hiraiko Seisakusho)).
80-1987), and the particle size distribution is measured by sieving 30 g of the sample for 10 minutes.
The particle size of is expressed as an average particle size. If there are many fractions of 45 μm or less, use an air jet sieve particle size analyzer (ALPI
The particle size distribution is measured using an NE-made air jet sieve A200LS type), and the cumulative particle size of 50% by weight is determined to be the average particle size.・ Apparent specific volume [cm ³ / g] 100 cm ³ of a glass graduated cylinder was used to sparsely fill the powder sample with a quantitative feeder or the like for 2 to 3 minutes,
Level the upper surface of the powder layer with a soft brush like a brush,
Read the volume. This is divided by the weight of the powder sample.
The weight of the powder sample is appropriately determined so that the volume is about 70 to 100 cm ³ .

Apparent tapping specific volume [cm ³ / g] After measuring the apparent specific volume, tapping is performed by hand on a table with a low impact such as a desk lined with a rubber plate. The tapping is performed by dropping it from a height of several cm vertically on the table until the compaction of the powder layer stops. After tapping, read the volume of the powder layer and divide by the powder sample weight.・ Average degree of polymerization [-] INDUSTRIAL AND ENGINEERIN
G CHEMISTRY Vol. 42, No. 3 p
502 to 507 (1950). Specific surface area [m ² / g] Measured by BET method using a flowsorb 2300 manufactured by Shimadzu Corporation and using nitrogen gas as an adsorption gas.

Adsorbed water lateral relaxation time [sec] Adsorbed water was adjusted to 5 to 6% (= 100 x water weight / (water weight + absolute dry sample weight)) and a powder sample was introduced into the solution sample tube. , Bruker FT-NMR (AC200P
Type), using a 1H solution NMR probe. The lateral relaxation time of adsorbed water is calculated by the following formula. Adsorption water transverse relaxation time = 1 / (obtained peak half width x
π) Crystalline Cellulose Confirmation Test 20 g of the powder sample is sifted for 5 minutes with an air jet sieve particle size distribution analyzer (Airjet Sieve A200LS type manufactured by ALPINE) equipped with a 38 μm mesh sieve. If 5% by weight or more remains on the sieve, add 30 g of powder sample to 270 m of water.
1 l, otherwise 45 g powder sample with 255 m water
Put in l. Then, this is dispersed by a disperser (WARING,
Blender 700 31BL46 type) 16000 ~
Stir at 18000 rpm for 5 minutes. 100 ml of dispersion
Was transferred to a 100 ml graduated cylinder and left standing for 3 hours, the liquid became white opaque and had no bubbles, and if separation of the liquid was not observed on the upper part, the powder sample was not cellulose powder but crystalline cellulose. Judge that there is.

Tablet weight [mg] and weight CV
[%] Ten tablets are precisely weighed, the number average value is the tablet weight, and the coefficient of variation is the weight CV.・ Tablet breaking strength [kgf] Schroingel tablet hardness tester (Freund Sangyo Co., Ltd.,
6D type) is applied in the diametrical direction of the tablet to express the load when the tablet is broken. The number of repetitions is 10, and the number average value is taken.・ Disintegration time [seconds] or [minutes] of tablets Perform the disintegration test according to the 12th Amended Japanese Pharmacopoeia, General Test Method, and Disintegration Test Method of Tablets. The collapse tester is Toyama Sangyo Co., Ltd.
Using NT-2HS type manufactured, the number average value of 6 samples is taken.

Tablet friability [%] The weight (Wa) of 20 tablets was measured, and this was placed in a tablet friability tester (Kayagaki Medical Science Co., Ltd.) and rotated at 25 rpm for 4 minutes. The fine powder adhering to the tablet is removed, the weight (Wb) is measured again, and the friability is calculated from the following formula. Friability = 100 x (Wa-Wb) / Wa-Drug dissolution rate [%] It was measured by a paddle method (100 rpm) using an automatic dissolution tester DT-600 manufactured by JASCO Corporation. The test liquid used was the Japanese Pharmacopoeia liquid I. The measurement was performed 3 times, and the average value was taken.

Example 1 Commercially available DP pulp was chopped into 1 pieces.
The acid-insoluble residue obtained by hydrolysis in a 0% hydrochloric acid aqueous solution at 105 ° C. for 30 minutes is filtered, washed, pH-adjusted, and concentration-adjusted to give a solid content concentration of 17% by weight, pH 6.4, and electric conductivity of 120 μS. / Cm, particles of 5 μm or less are 3.0%, 1
An aqueous dispersion of cellulose particles having a particle size of 00 μm or more of 5.2% was obtained. Drum dryer (KDD-Kusuki Seisakusho KDD-
Type 1, steam pressure 3.5 kgf / cm ² , drum surface temperature 136 ° C., drum rotation speed 2 rpm, water dispersion temperature of reservoir 100 ° C.), then crushed with a hammer mill and coarse particles with a sieve of 425 μm. Except that a sample A was obtained.
When the confirmation test was performed on sample A, it was white opaque and had no bubbles,
Moreover, it became a gel-like dispersion liquid without water separation. Table 1 shows the basic physical properties of Sample A.

(Example 2) Commercially available KP pulp was shredded, and the acid-insoluble residue obtained by treating in the same manner as in Example 1 was filtered, washed, pH-adjusted and concentration-adjusted to obtain a solid content concentration. 21
% By weight, pH 8.4, electric conductivity 275 μS / cm, 5
An aqueous dispersion of cellulose particles having 4.2% of particles having a size of not more than μm and 5.9% having particles having a size of 100 μm or more was obtained. This was dried with a drum dryer (steam pressure 1.2 kgf / cm ² , drum surface temperature 110 ° C., drum rotation speed 0.5 rpm, reservoir water dispersion temperature 99 to 100 ° C.), and then pulverized with a hammer mill, Remove coarse particles with a 425 μm sieve,
Sample B was obtained. When the confirmation test was performed on Sample B, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 1 shows the basic physical properties of Sample B.

Example 3 The acid-insoluble residue obtained in the same manner as in Example 1 was filtered, washed, adjusted in pH and adjusted in concentration to give a solid content concentration of 18% by weight, a pH of 7.2 and an electric conductivity of 8.
Particles of 4 μS / cm, 5 μm or less 7.1%, 100 μ
An aqueous dispersion of cellulose particles having 2.1% or more of particles of m or more was obtained. Spray dryer (using a two-fluid nozzle, steam is used as the fluid to atomize the water dispersion, spray pressure 4 kgf
/ Cm ² , about 150 ° C), and then open 42
Sample C was obtained by removing coarse particles with a 5 μm sieve. When the confirmation test was performed on the sample C, it was a gel-like dispersion liquid which was white and opaque, had no bubbles, and had no water separation. Table 1 shows the basic physical properties of Sample C.

Comparative Example 1 Commercially available DP pulp was chopped into 1 pieces.
The acid-insoluble residue obtained by hydrolysis in a 0% hydrochloric acid aqueous solution at 105 ° C. for 30 minutes was filtered and washed to obtain particles having a solid content concentration of 45% by weight, pH 3.6, and an electric conductivity of 40 μS / cm, 5 μm or less. 1.1%, particles of 100 μm or more 10.2
% Aqueous dispersion of cellulose particles was obtained. This was dried at 80 ° C. in a tray hot air drier, crushed with a hammer mill, and coarse particles were removed with a sieve having an opening of 425 μm to obtain sample D. When a confirmation test was performed on Sample D, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 1 shows the basic physical properties of Sample D. (Comparative Example 2) The sample obtained in Comparative Example 1 was crushed by an air flow type crusher (manufactured by Seishin Enterprise Co., Ltd., single track jet mill STJ-200 type) while changing the sample supply amount, and then the method of Japanese Patent Laid-Open No. 63- Samples E and F corresponding to the invention products described in 267731 were obtained. When the confirmation test was conducted on the sample E, it was a white opaque gel-free dispersion liquid without water separation, but the sample F had water separation on the upper part. Table 1 shows the basic physical properties of Samples E and F.

(Comparative Example 3) Commercially available SP pulp was chopped into 1 pieces.
Acid insoluble residue obtained by hydrolysis in 99% sulfuric acid aqueous solution at 99 ° C. for 30 minutes is filtered and washed, solid content concentration 49 weight%, pH 3.82, electric conductivity 45 μS / cm, 5 μm
0.9% of the following particles and 20% of particles of 100 μm or more.
A 4% aqueous dispersion of cellulose particles was obtained. This was dried at 80 ° C. in a tray hot air dryer. Average degree of polymerization of dried product is 4
It was 52. Subsequently, this was crushed with a hammer mill and further crushed with a porcelain ball mill for 12 hours, with an opening of 425μ.
Coarse particles were removed with a sieve of m to obtain a sample G corresponding to the invention product described in JP-B-51-17172. When the confirmation test was performed on sample G, water separation occurred at the upper part. Table 1 shows the basic physical properties of Sample G.

[0067]

[Table 1]

(Examples 4 to 6) Samples A, B, C and 150
g and lactose (DMV, Pharmatose 100
M) 600 g were mixed in a plastic bag for 3 minutes, and then magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) 3.75
The mixture was added with g and further mixed for 30 seconds, and the mixture was mixed with a rotary tableting machine (manufactured by Kikusui Seisakusho, CLEANPRESS CO.
RRECT 12HUK) was punched at a turntable rotation speed of 25 rpm using an 8 mmφ, 12R punch to obtain a tablet having a weight of 200 mg. Table 2 shows the physical properties of the tablets. (Comparative Examples 4 to 6) Instead of Samples A, B and C, Sample D,
Tableting was performed using E and G in the same manner as in Use Example 1. Table 2 shows the physical properties of the obtained tablets.

[0069]

[Table 2]

From the results shown in Table 2, it can be seen that when Sample E is used (Comparative Example 5), the breaking strength increases as the tableting pressure increases, but the disintegration time also becomes extremely long.
Further, in the case of Samples D and G (Comparative Examples 4 and 6), it is found that even if the tableting pressure is increased, the disintegration time is not so long, but the breaking strength is not so much increased. In contrast, when the product of the present invention is used (Examples 4 to 6), the tableting pressure increases and the breaking strength of the tablet also remarkably increases, but the disintegration time remains short. Especially the breaking strength of standard tablets is 11kgf
The samples A and C (Examples 4 and 5) as described above have high fracture strength. From these facts, it is understood that, by using the present invention, a tablet having high breaking strength and rapidly disintegrating can be easily prepared.

Example 7 Commercial DP pulp was chopped into 4 pieces.
Of the acid-insoluble residue obtained by hydrolysis at 105 ° C. for 3 hours in a 15% sulfuric acid aqueous solution is filtered, washed, pH-adjusted and concentration-adjusted to obtain a solid content concentration of 17% by weight, pH 6.0 and electric conductivity of 6.
2μS / cm, 5.6% of particles of 5μm or less, 100μ
An aqueous dispersion of cellulose particles containing 3.1% of m or more particles was obtained. This aqueous dispersion was dried in the same manner as in Example 1, pulverized with a hammer mill, and coarse particles were removed with a sieve having an opening of 425 μm to obtain Sample H. When the confirmation test was performed on Sample H, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 3 shows the basic physical properties of Sample H.

(Example 8) The acid-insoluble residue obtained in the same manner as in Example 1 was filtered, washed, pH-adjusted and concentration-adjusted,
Solid content concentration 18% by weight, pH 7.3, electric conductivity 113
μS / cm, 3.5% of particles of 5 μm or less, 100 μm
An aqueous dispersion of cellulose particles having the above particles of 4.9% was obtained. This water dispersion was placed in a high-pressure sterilizer (autoclave), the system temperature was kept at 121 ° C. for 2 hours, the temperature of the water dispersion was raised to 120 ° C. or higher, then allowed to cool and taken out. At this time, an irreversible temperature control material (Thermo Label Super Nimi 3K-11, manufactured by NOF Giken Co., Ltd.) was placed inside the water dispersion.
0) was added and it was confirmed that the temperature was at least 120 ° C or higher. The temperature of the aqueous dispersion when taken out was 95 ° C. This water dispersion was thinly spread on a glass plate to a thickness of about 1 mm, dried at 80 ° C. in a tray hot air dryer, peeled and ground with a hammer mill, and coarse particles were removed with a sieve having an opening of 425 μm. , Sample I was obtained. When the confirmation test was conducted on Sample I, it was a gel dispersion liquid which was white opaque, had no bubbles, and had no water separation. Table 3 shows the basic physical properties of Sample I.

(Comparative Example 7) The same operation as in Example 1 was conducted except that the hydrolysis time was changed to 5 minutes, and the solid content concentration was 17% by weight, the pH was 8.1, the electric conductivity was 38 μS / cm, and 5 μm.
0.1% of the following particles and 22.
A 3% aqueous dispersion of cellulose particles was obtained. This is Example 1
The dried unpulverized product obtained in the same manner was pulverized with a pulverizer (Flash Mill FL-200 manufactured by Fuji Paudal Co., Ltd.), coarse particles were removed with a sieve having an opening of 425 μm, and Sample J was obtained. Obtained. When the confirmation test was performed for sample J, water separation occurred in the upper part. Table 3 shows the basic physical properties of Sample J.

(Comparative Example 8) Rayon yarn waste was shredded,
The acid-insoluble residue obtained by hydrolysis in a 0.3% hydrochloric acid aqueous solution at 100 ° C. for 40 minutes was washed by decantation, filtered, adjusted in pH, adjusted in concentration, solid content concentration was 10% by weight, and pH was 7. 3, electric conductivity 310μS / cm, 5μm
The following particles were 19.3%, and particles of 100 μm or more were 0.
A 0% aqueous dispersion of cellulose particles was obtained. This water dispersion was dried in the same manner as in Example 1 and then pulverized with an airflow pulverizer,
Coarse particles were removed with a sieve having an opening of 425 μm to obtain Sample K. When the confirmation test was performed for sample K, water separation occurred at the upper part.
Table 3 shows the basic physical properties of Sample K.

Comparative Example 9 The acid-insoluble residue obtained in the same manner as in Comparative Example 1 was filtered, washed and dehydrated to obtain a wet cake having a water content of 50%. This wet cake has a pH of 3.5,
The electrical conductivity was 41 μS / cm, particles of 5 μm or less were 1.3%, and particles of 100 μm or more were 12.4%. This was dispersed in isopropyl alcohol, filtered, deliquored, and redispersed twice, and further 400 kgf / in a Gorin homogenizer 15M type manufactured by Nippon Seiki Seisakusho Co., Ltd.
The dispersion treatment was performed three times at a treatment pressure of cm ² . Isopropyl alcohol was added to this slurry to adjust the solid content concentration to 10% by weight, and then spray drying was performed with a nitrogen circulation type spray dryer (blast temperature 150 ° C., exhaust air temperature 8
3 ° C.), and coarse particles were removed with a sieve having an opening of 425 μm to obtain a sample L corresponding to the invention product described in JP-A-2-84401. The total volume of pores of sample L having a diameter of 0.01 μm or more (measured by a mercury porosimeter) is 0.7 cm.
It was ³ / g. When the confirmation test was performed on Sample L, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 3 shows other basic physical properties of the sample L.

(Comparative Example 10) Commercially available DP pulp was shredded,
The acid-insoluble residue obtained by hydrolysis in a 0.5% hydrochloric acid aqueous solution at 121 ° C. for 1 hour was filtered, washed, and dehydrated to obtain a solid content concentration of 48% by weight, pH 3.4, and an electric conductivity of 53 μS / c.
Thus, an aqueous dispersion of cellulose particles in which 3.2% of particles having a size of 5 μm or less and 3.2% of particles having a size of 100 μm or more were obtained. This was dried at 70 ° C. in a vacuum dryer to obtain a dried product having a water content of 4.2%. This is crushed with a hammer mill and the opening is 425μ.
Coarse particles were removed with a sieve of m to obtain a sample M corresponding to the invention product described in JP-B-40-26274. When the confirmation test was performed on Sample M, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 3 shows the basic physical properties of Sample M.

[0077]

[Table 3]

(Examples 9 and 10) Samples H and I (70 g) and lactose (DMV, Pharmatose 100M) 6
Using 30 g and 3.5 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.), tableting was performed in the same manner as in Use Example 1. Table 4 shows the physical properties of the obtained tablets. (Comparative Examples 11 to 14) Sample J, instead of Samples H and I,
Tableting was performed using K, L and M in the same manner as in Use Example 4. Table 4 shows the physical properties of the obtained tablets.

[0079]

[Table 4]

From the results shown in Table 4, it can be seen that when Sample L is used (Comparative Example 13), the breaking strength increases as the tableting pressure increases, but the disintegration time also becomes extremely long.
In the case of using sample J (Comparative Example 11), the breaking strength does not increase so much even when the tableting pressure is increased, but the disintegration is long, and since the average particle size is larger than 120 μm, the tableting powder is used. Has a low fluidity, which reflects the tablet weight CV
Is high. When Samples K and M are used (Comparative Example 1)
In No. 2, 14), even if the tableting pressure is increased, the disintegration time is very short, but the breaking strength is not so high. On the other hand, when the samples H and I of the present invention were used (Examples 9 and 1)
In 0), although the compounding amount was about 10% by weight, the tableting pressure increased and the breaking strength of the tablet significantly increased, but the disintegration time was relatively short and the weight CV was low. It can be seen that it is possible to produce tablets with high breaking strength, rapid disintegration and high weight uniformity with a small amount of addition.

(Example 11) The acid-insoluble residue obtained in the same manner as in Example 1 was filtered, washed, adjusted in pH and adjusted in concentration to obtain a solid content concentration of 19% by weight, a pH of 6.6 and an electric conductivity of 1.
25 μS / cm, 3.2% of particles of 5 μm or less, 100%
An aqueous dispersion of cellulose particles having a particle size of μm or more of 5.2% was obtained. This water dispersion was placed in a drum dryer (steam pressure 5k
gf / cm ² , drum surface temperature 143 ° C., drum rotation speed 5 rpm, and water dispersion temperature of reservoir 100 ° C.)
Crusher (Fuji Mill FL-2 made by Fuji Paudal Co., Ltd.)
00 type), and coarse particles were removed with a sieve having an opening of 425 μm to obtain sample N. When a confirmation test was performed on Sample N, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 5 shows the basic physical properties of Sample N.

(Example 12) The purified linter was sufficiently loosened, and the acid hydrolysis residue obtained by the same treatment as in Example 1 was filtered, washed, adjusted in pH and adjusted in concentration to give a solid content of 20% by weight. , PH 8.2, electric conductivity 54 μS / cm,
An aqueous dispersion of cellulose particles having 5% or less particles of 0.3% and 100 μm or more particles of 15.3% was obtained. This water dispersion was applied to a drum dryer (steam pressure 3 kgf / cm ² ,
After being dried at a drum surface temperature of 131 ° C., a drum rotation speed of 1 rpm, and a reservoir water dispersion temperature of 99 to 100 ° C.), the mixture was ground with a hammer mill and coarse particles were removed with a sieve having an opening of 425 μm to obtain Sample O. When a confirmation test was performed on Sample O, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 5 shows the basic physical properties of Sample O.

(Comparative Example 15) The same operation as in Example 1 was carried out except that the hydrolysis time was changed to 5 minutes.
% By weight, pH 6.5, electric conductivity 100 μS / cm, 5
0.2% of particles of less than μm, 2 of particles of more than 100 μm
A 3.0% aqueous dispersion of cellulose particles was obtained. This was again operated in the same manner as in Example 1 to obtain a sample P. When the confirmation test was performed on the sample P, water separation occurred in the upper portion. Table 5 shows the basic physical properties of Sample P. (Comparative Example 16) Commercially available crystalline cellulose (Avicel <registered trademark> PH-101, manufactured by Asahi Kasei Kogyo Co., Ltd.) was used as Sample Q. When a confirmation test was performed on Sample Q, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Sample Q
The basic physical properties of are shown in Table 5.

Comparative Example 17 Commercially available crystalline cellulose (Avicel <registered trademark> PH-301, Asahi Kasei Kogyo Co., Ltd.)
Was manufactured as a sample R. The angle of repose of sample R is 41 degrees,
It corresponds to the invention product described in JP-B-56-38128. When a confirmation test was performed on Sample R, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 5 shows the basic physical properties of Sample R. (Comparative Example 18) Commercially available crystalline cellulose (GRADE M
-101, MING TAI CHEMICAL C
O. , LTD. (Manufactured) was used as sample S. When a confirmation test was performed on Sample S, it was a gel dispersion liquid that was white opaque, had no bubbles, and had no water separation. Table 5 shows the basic physical properties of the sample S.

[0085]

[Table 5]

(Examples 13 and 14) Samples N, O and 150
g and phenacetin (Yamamoto Chemical Co., Ltd.) 150 g and lactose (DMV, Pharmatose 100M) 450
g in a plastic bag for 3 minutes, then 3.75 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) was added and further mixed for 30 seconds.
CLEANPRESS CORRECT manufactured by Kikusui Seisakusho
12HUK), tabletted at a turntable rotation speed of 25 rpm with a punch of 8 mmφ and 12R, and weighs 200 mg.
To obtain tablets. Table 6 shows the physical properties of the tablets. (Comparative Examples 19 to 23) Instead of Samples N and O, Sample F,
Tableting was performed using P, Q, R and S in the same manner as in Use Example 6. Table 6 shows the physical properties of the obtained tablets.

[0087]

[Table 6]

From the results in Table 6, it can be seen that when Sample F is used (Comparative Example 19), the breaking strength increases with the increase in tableting pressure, but the disintegration time also becomes extremely long. In addition, since the sample F has a small average particle size and is bulky (the apparent specific volume is large), the fluidity of the tableting powder is low, and the tablet weight CV is high reflecting this. When Sample P is used (Comparative Example 20), even if the tableting pressure is increased, the disintegration time is very short, but the breaking strength is not so high. Similar results were obtained when using commercially available crystalline cellulose samples Q, R, and S (Comparative Examples 21, 22, and 23).
On the other hand, samples N and O (Example 13,
In 14), the tableting pressure increases significantly with the tablet breaking strength, but the disintegration time remains short and the tablet weight CV is low. Therefore, the tablet has high breaking strength, rapid disintegrating property, and It can be seen that it is possible to easily prepare a tablet having high tablet weight uniformity.

(Examples 15 to 17) Samples A, B, I and 4
90 g, cocoa powder 500 g, and light anhydrous silicic acid (Aerosil 200, Nippon Aerosil) 10 g were mixed in a plastic bag for 3 minutes, and then magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) 5 g was added and further mixed for 30 seconds. To
Rotary tableting machine (Kikusui Seisakusho, CLEANP)
8mmφ with RESS COLRECT 12HUK),
Turntable rotation speed 24 rpm using 12R punch
The tablets were compressed with to give tablets weighing 180 mg. Table 7 shows the physical properties of the tablets.

Comparative Examples 24 to 27 Tablets were compressed in the same manner as in Example 15 except that Samples D, E, G and Q were used instead of Samples A, B and I. Tablets could be tableted using Samples D, G and Q, but tableting could not be performed using Sample E (Comparative Example 25) because the flow of the mixed powder was poor. Sample D,
Table 7 shows the physical properties of the tablets obtained by using G and Q.

[0091]

[Table 7]

From the results of Table 7, in the case of using the samples D, G and Q (Comparative Examples 24, 26 and 27), the hardness of the tablets did not increase even when the tableting pressure was increased, and the practically required minimum of 4 kg was obtained. While it barely exceeds, when Samples A, B, and I (Examples 15 to 17) were used, the tableting pressure was 400 kgf or more and the tablet hardness exceeded 4 kg. It is clear that there is a significant improvement. (Examples 18 and 19) Samples A and B, 800 g, and windproof Tsushosan extract powder (Koutsushosan dried extract-AM, Nippon Powder Chemicals Co., Ltd.) 200 g and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.). 5 g is used, and the rest is Example 1
Tableting was performed in the same manner as in (1) to give a tablet weighing 200 mg. Table 8 shows the physical properties of the obtained tablets.

Comparative Examples 28 and 29 Tablets were compressed in the same manner as in Example 18 except that Samples E and Q were used instead of Samples A and B. When sample Q was used (Comparative Example 29), tableting was possible, but when sample E was used (Comparative Example 28), tableting could not be performed because the flow of the mixed powder was poor. Table 8 shows the physical properties of the obtained tablets.

[0094]

[Table 8]

From the results shown in Table 8, the tablet hardness is clearly higher in the samples A and B (Examples 18 and 19) than in the sample Q. When samples A and B are used, the tablet disintegration is slightly inferior, but since the compression moldability is high, the required tablet hardness can be obtained even if the compounding amount is reduced. Can be improved.

(Examples 20 to 22) Phenacetin (Yamamoto Chemical Co., Ltd.) 350 g, lactose (200 M, DMV) 10
0 g and 50 g of corn starch (Nippon Starch Chemical Co., Ltd.) were weighed out, put in a polyethylene bag, and shaken for 1 minute.
This was put in a planetary mixer (Shinagawa Kogyosho, Universal Mixer 5DMr type) equipped with a stirring paddle, and 90 g of 3% hydroxypropyl cellulose (Nippon Soda, HPC-M) aqueous solution was gradually added while stirring at low speed. After the addition was completed, the mixture was mixed for 3 minutes and further mixed at high speed for 12 minutes.
The granulated product was sieved with a sieve having an opening of 1410 μm to remove coarse particles, and then dried at 40 ° C. for 16 hours using a tray hot air dryer to obtain granules. The same operation was performed a total of 8 times, and the obtained granules were mixed and put together into a granule A.
Granule A is 0% at 1410 μm or more, 710-1410 μm
m is 10.5%, 500-710 μm is 14.9%, 3
0 to 500 μm is 33.9%, 177 to 300 μm is 21.2%, 177 μm or less is 19.5%, and the average particle size is 357 μm, and the coarse specific volume thereof is 1.92 cm ³ / g. Met. 450 g of these granules, 40 g of samples A, B, I, 5 g of croscarmellose sodium (“Ac-Di-Sol”, manufactured by FMC) and 5 g of light anhydrous silicic acid (Aerosil 200, Nippon Aerosil) 3 in a plastic bag Mix for a minute, then add 2.5 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) for another 30 minutes.
The mixture for 2 seconds was mixed with a rotary tableting machine (CLEANPRESS CORRECT 12 manufactured by Kikusui Seisakusho KK).
HUK) was tableted at a turntable rotation speed of 24 rpm using a punch of 8 mmφ and 12R to obtain a tablet having a weight of 200 mg. Table 9 shows the physical properties of the tablets.

Comparative Examples 30 to 33 450 g of the granules prepared in Example 20 and 40 g of samples D, E, G, Q and croscarmellose sodium (“Ac-Di-Sol”, F)
Tableting was performed in the same manner as in Example 20 except that 10 g (manufactured by MC) was used. Table 9 shows the physical properties of the obtained tablets. (Comparative Example 34) 500 g of the granules prepared in Example 20 and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) 2.
The mixture obtained by adding 5 g and further mixing for 30 seconds was tableted in the same manner as in Example 20. Table 9 shows the physical properties of the obtained tablets.

[0098]

[Table 9]

From the results shown in Table 9, tableting was carried out in combination with known excipients and additives (Comparative Examples 30 to 3).
3) is obtained by tableting a mixture of granules and a lubricant (Comparative Example 3).
Compared with 4), compression moldability and disintegration are improved to some extent, but in the case of the present invention (Examples 30 to 33), compression moldability is further improved and disintegration is improved. Is clear.

Examples 23 and 24 295 g of sodium salicylate (Junsei Pharmaceutical Co., Ltd.), lactose (200 M, DMV)
Company) 125 g, corn starch (Nippon Starch Chemical) 3
2.5 g, crystalline cellulose (Asahi Kasei, Avicel <registered trademark> PH-101,) 45 g, and hydroxypropyl cellulose (Nippon Soda, HPC-L) 2.5 g were used instead of the 3% hydroxypropyl cellulose aqueous solution for purification. Granule B was obtained in the same manner as in Granule A except that 42.5 g of water was used. Granule B has a particle size of 1410 μm or more of 0.
4%, 710 to 1410 μm 16.1%, 500 to 7
10 μm is 25.2%, 300 to 500 μm is 35.2%
%, 177 to 300 μm was 15.5%, 177 μm or less was 7.6%, the average particle size was 453 μm, and the coarse specific volume was 1.48 cm ³ / g. 425 g of the granules, 50 g of samples A and B, and 25 g of croscarmellose sodium (“Ac-Di-Sol”, manufactured by FMC) were mixed in a plastic bag for 3 minutes, and then magnesium stearate (Tahira Science & Industry Co., Ltd.). (Made by Kikusui Seisakusho Co., Ltd., CLEANPRESS COR)
RECT 12HUK) with a punch of 8 mmφ, 12R and tableting at a turntable rotation speed of 24 rpm.
A 00 mg tablet was obtained. Table 10 shows the physical properties of the tablets.

Comparative Example 35 Tableting was performed in the same manner as in Example 23 except that Sample Q was used instead of Samples A and B. Table 10 shows the physical properties of the obtained tablets. (Comparative Example 36) 500 g of the granules prepared in Example 23 and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.)
The mixture was added with 5 g and further mixed for 30 seconds, and the mixture was tableted in the same manner as in Example 4. Table 10 shows the physical properties of the obtained tablets.

[0102]

[Table 10]

From the results shown in Table 10, the disintegration was improved in the case of using the known excipient (Comparative Example 35) as compared with the case of tableting the mixture of the granules and the lubricant (Comparative Example 36). However, the compression moldability is not so improved. On the other hand, in the case of the present invention (Examples 23 and 24), not only the disintegration property but also the compression moldability is clearly improved.

(Examples 25 and 26) Samples A, H and 1 kg
1 kg of lactose (200M, DMV) and 3 kg of phenacetin (Yamamoto Chemical Co., Ltd.) were mixed in a plastic bag for 3 minutes, and then magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.)
10 g was added and mixed gently for 30 seconds. This mixed powder is dried with a dry granulator (Hosokawa Micron Co., Ltd., Pharmapactor L200 / 50P type, concave lateral groove roll is used, straight screw is used), and the roll speed is 5 rpm.
Then, the screw rotation speed was adjusted so that the action stress between the rolls was 3 tons, and a compressed sheet was obtained. This was crushed with a dry granulator (Shirai Matsuki Kikai Co., Ltd., ERWEKA),
After sieving with a sieve having an opening of 1410 μm, the on portion was crushed again. 5 to 8 until the ON content falls below approximately 10% by weight
The granules for tableting were obtained by crushing and removing the ON content. 1.5 g of magnesium stearate was added to 500 g of the granules for tableting.
The mixture was added with g and further mixed for 30 seconds, and the mixture was mixed with a rotary tableting machine (manufactured by Kikusui Seisakusho, CLEANPRESS CO.
RRECT 12HUK) was used for tableting at a turntable rotation speed of 24 rpm using an 8 mmφ, 12R punch to obtain a tablet having a weight of 200 mg. Table 11 shows the physical properties of the tablets. (Comparative Examples 37 and 38) Samples M and R instead of Samples A and H
The same procedure as in Example 25 was performed thereafter, and tableting was performed. Table 11 shows the physical properties of the obtained tablets.

[0105]

[Table 11]

From the results in Table 11, the present invention (Example 25, Example 25, Comparative Example 37, 38) was compared with the case of using known excipients (Comparative Examples 37, 38).
No. 26) has a high tablet hardness and a significantly reduced tablet friability. (Example 27) Spherical granules of crystalline cellulose (Selphia <
Registered trademark> CP-305, Asahi Chemical Industry Co., Ltd.) 20k
g is a rolling flow device (multiplex MP-25 type,
(Manufactured by Paulec Co., Ltd.), the blade rotation speed 240 rpm, air supply amount 7 m ³ / min, air supply temperature 75
Hydroxypropyl cellulose (HPC-LEP, Shin-Etsu Chemical Co., Ltd.) 2
By weight, 4.1 kg of an aqueous solution containing 10% by weight of vitamin B2 (Nippon Roche Co., Ltd.) was sprayed tangentially at 4.1 kg at a rate of 88 g / min and dried to obtain spheroidal granules containing 2% by weight of vitamin B2. It was ("Tangential"
Means the position and direction of the spray gun that sprays, and is the same as the rotation of the blade at the position where the particles for rolling motion have a relatively high particle density, that is, in the space slightly above the blade at the bottom of the device. (Set the spray gun to spray the coating liquid in one direction)

1.5 kg of the spherical elementary granules were charged into a tumbling flow device (Multiplex MP-01 type, manufactured by Paulec Co., Ltd.), which was rotated at a blade rotation speed of 380 rpm, an air supply amount of 75 m ³ / hr, and an air supply temperature. 75 ℃, exhaust temperature 35 ℃
It rolls and flows at a film coating liquid of 21 g / mi
At a rate of n, 564 g was tangentially sprayed and dried. The coated granules were heat-treated at 80 ° C. for 1 hour in a hot air dryer. The film coating solution is an aqueous suspension type film coating agent (Aquacoat E
Triethyl citrate (Citroflex <registered trademark> 2 SC for 100 parts by weight of CD-30, manufactured by FMC)
-60, Fizer Co., Ltd. 7.5 parts by weight was added, and the mixture was dispersed for 1 hour with a homomixer, then 80 parts by weight of pure water was added and lightly stirred. Table 12 shows the dissolution rate of vitamin B2 from the coated granules after 4 hours. (By the way, no difference was observed in the dissolution rate between these granules regardless of whether the test solution was solution I or solution II, so the subsequent measurements were carried out with solution I).

To 280 g of the granules, 120 g of sample A was added, mixed in a plastic bag for 3 minutes, further added with 2 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.), and slowly mixed for 30 seconds. Tablet press (CLEANPRESS COR manufactured by Kikusui Seisakusho Co., Ltd.)
RECT 12HUK) was pressed with a 12 mmφ punch at a turntable rotation speed of 24 rpm and a tableting pressure of 500 kgf to obtain a tablet containing coated granules having a weight of 600 mg. Table 12 shows the physical properties of the tablets and the dissolution rate of vitamin B2 after 4 hours. (Example 28) Using the coated granules (280 g) prepared in Example 27 and Sample H (120 g), the tableting pressure was 550 k.
A tablet containing coated granules was obtained in the same manner as in Example 27 except that gf was used. Table 12 shows the physical properties of the tablets and the dissolution rate of vitamin B2 after 4 hours.

(Comparative Example 39) A coated granule-containing tablet was obtained in the same manner as in Example 27 except that 280 g of the coated granule prepared in Example 27 and 120 g of sample M were used, and the tableting pressure was 700 kgf. . Table 12 shows the physical properties of the tablets and the dissolution rate of vitamin B2 after 4 hours. (Comparative Example 40) Using 280 g of the coated granules prepared in Example 27 and 120 g of sample R, the tableting pressure was 800 k.
A tablet containing coated granules was obtained in the same manner as in Example 27 except that gf was used. Table 12 shows the physical properties of the tablets and the dissolution rate of vitamin B2 after 4 hours.

[0110]

[Table 12]

As can be seen from Table 12, the tableting pressure was adjusted so that the strength of each tablet was adjusted to the practical strength of about 5 kgf. In the present invention, molding was possible even when the tableting pressure was low ( In contrast to Examples 27 and 28), it was necessary to increase the tableting pressure when using a known excipient (Comparative Example 3).
9, 40). Therefore, in the present invention, the coating film was not damaged, and the elution property of vitamin B2 was similar to that of the coated granules. However, when a known excipient was used, the coating film was damaged and the elution property was remarkably increased. I got it.

(Example 29) Ethenzamid (Iwaki Pharmaceutical Co., Ltd.)
100 g, lactose (200 M, DMV) 700 g, corn starch (Nippon Starch Chemical) 100 g, sample C, 10
Weighing 0g, high speed mixing granulator (manufactured by Gohashi Seisakusho, NS
K250 type), stirring blade rotation speed 500 rp
Mix well by spinning for 1 minute at m, then 6
% Hydroxypropyl cellulose (Nippon Soda, HPC-
L) 200 g of the aqueous solution was added over 1 minute, and granulation was performed for 5 minutes after the addition was completed. This was dried at 40 ° C. for 15 hours to obtain a granulated product. Coarse particles of granulated product (+ 1410μ
m) is 5.5%, and the particle size distribution of the components excluding it is 2.7% at +710 μm, 2.0% at 500 to 710 μm, 8.9% at 300 to 500 μm, and 177 to 3
00 .mu.m is 43.2%, 105-177 .mu.m is 34.1%.
%, 74-105 μm is 7.5%, -74 μm is 1.6
%, The crude specific volume was 2.09 cm ³ / g. 500 g of these granules and 2.5 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed in a plastic bag for 30 seconds, and then rotary tableting machine (Kikusui Seisakusho, CLEANPRE).
8 mmφ, 12 with SS COLRECT 12HUK)
Tableting was performed using an R punch at a turntable rotation speed of 24 rpm to give a tablet having a weight of 200 mg. Table 13 shows the physical properties of the tablets.

(Comparative Example 41) Granulation was performed in the same manner as in Example 29 except that Sample Q was used instead of Sample C. The coarse particles (+1410 μm) of the obtained granulated product were 6.9%, and the particle size distribution of the components excluding it was +710 μm of 2.3.
%, 500-710 μm is 1.5%, 300-500 μm
m is 4.8%, 177 to 300 μm is 31.4%, 10
5 to 177 μm is 44.3%, 74 to 105 μm is 1
2.1%, -74 μm 3.6%, crude specific volume 1.88
It was cm ³ / g. The granules were tableted in the same manner as in Example 29. Table 13 shows the physical properties of the obtained tablets.

[0114]

[Table 13]

The granules of Example 29, which is a product of the present invention, had a larger crude specific volume than the granules of Comparative Example 41, which is a conventional technique, and it was expected that the tableted product had higher moldability.
The tableting results are shown in Table 13, and again, the granules of Example 29 had high moldability, and the effect of the present invention was confirmed.

[0116]

INDUSTRIAL APPLICABILITY Since the present invention is excellent in compression moldability, it can be molded with a small amount of compound when applied to tablet molding.
It is useful when there are restrictions on the formulation of excipients such as small tablets and cold remedies. Further, since it can be molded with a low compression force, it is also useful when high compression force such as a granule-containing tablet must be avoided. Furthermore, since it is also excellent in disintegrability, it is possible to produce tablets without particularly blending a disintegrant.

Continuation of front page (31) Priority claim number Japanese Patent Application No. 6-204170 (32) Priority date August 8, 1994 (August 1994) (33) Priority claim country Japan (JP) (72) Inventor Tetsuya Otani 6-4100 Asahi-cho, Nobeoka-shi, Miyazaki Prefecture Asahi Kasei Kogyo Co., Ltd. (72) Inventor Yosuke Honda, Asahi-kasei Kogyo Co., Ltd. 6-4100 Asahi-cho, Nobeoka-shi Miyazaki (56) References JP-A-54-20126 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 47/38

Claims (11)

(57) [Claims] 1. A pharmaceutical active ingredient powder, a) an average degree of polymerization of 150 to 220, and b) an apparent specific volume of 4.0 to 6.0.
cm ³ / g, c) Apparent tapping specific volume is 2.4 cm
³ / g or more, d) specific surface area of less than 20 m ² / g, e) acetic acid retention of 280% or more, f) less than 5% by weight of particles of 355 μm or more, and average particle size of 30 to 120 μm Has a distribution, g) the compression characteristics shown by the following formula (1), and h) weighs 500 mg, and then weighs 100 k
A columnar molded article having a bottom surface area of 1 cm ² obtained by compressing at gf / cm ² for 10 seconds has a compression molding property such that the breaking strength in the diametrical direction is 10 kgf or more and the collapse time is within 100 seconds. A pharmaceutical composition comprising crystalline cellulose having [Equation 1] (However, a = 0.85-0.90, b = 0.05-0.
10 and P is the compression pressure of the powder [kgf / cm
² ], V ₀ is the apparent specific volume of the powder [cm ³ / g], V is the specific volume of the powder or tablet at the compression pressure P [cm ³
/ G]) 2. Crystalline cellulose has an adsorbed water content of 5 to 6%.
2. The pharmaceutical composition according to claim 1, which has a lateral relaxation time of adsorbed water of 0.00024 seconds or less (measured by a proton NMR spectrum method using a 1H solution NMR probe). .. 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet obtained by a direct powder compression method. 4. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a granule obtained by a dry granulation method, or a tablet obtained by compression molding the granule. 5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a granule obtained by a wet granulation method or a tablet obtained by compression molding the granule. 6. The pharmaceutical composition is a granule obtained by a dry granulation method or a granule obtained by a wet granulation method and a tablet obtained by compression-molding the crystalline cellulose according to claim 1. The pharmaceutical composition according to claim 1 or 2. 7. A pharmaceutical composition comprising granules obtained by a dry granulation method or granules obtained by a wet granulation method, and tablets obtained by compression molding crystalline cellulose according to claim 1 and other tablet raw material powders. The pharmaceutical composition according to claim 1 or 2, which is characterized in that 8. The pharmaceutical composition according to claim 7, wherein a disintegrant and a fluidizing agent are used as the other powdered raw materials for tablets. 9. The pharmaceutical composition according to claim 1 or 2, wherein the medicinal ingredient powder is a Chinese herb powder or a crude drug powder. 10. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a capsule obtained by a capsule filling method utilizing the compression moldability of powder. 11. The pharmaceutical composition according to claim 4, which is a granule having a coating film.